Breast carcinoma pathology


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Breast carcinoma pathology

  1. 1. Dr. P. Karpagam Kiruba Rajeswari, M.B.B.S.,D.C.P., Tutor in Pathology, MAPIMS
  2. 2. <ul><li>Most common non-skin malignancy in women!!! </li></ul>
  4. 7. PATHOGNESIS – GENETIC FACTORS <ul><li>Most common genes implicated in Breast carcinoma </li></ul>
  5. 8. BRCA -1  Breast Cancer 1,Early onset ( Chr.17) BRCA-2, Breast Cancer 2,Early onset( Chr.13) p53( Chr.17) CHEK2( Chr. 22) <ul><li>FUNCTIONS: </li></ul><ul><li>Transcription </li></ul><ul><li>DNA Repair of double stranded breaks </li></ul><ul><li>Ubiquitination </li></ul><ul><li>Transcriptional regulation. </li></ul><ul><li>FUNCTIONS: </li></ul><ul><li>Stability of the human genome </li></ul><ul><li>DNA double strand break repair. </li></ul><ul><li>FUNCTIONS </li></ul><ul><li>Cell cycle control </li></ul><ul><li>DNA replication </li></ul><ul><li>DNA repair </li></ul><ul><li>Apoptosis. </li></ul><ul><li>FUNCTIONS </li></ul><ul><li>Cell cycle checkpoint kinase, recognition and repair of DNA damage. </li></ul><ul><li>Activates BRCA1 and p53 by phosphorylation </li></ul>Germline point mutations/Deletions of BRCA1 gene  Hereditary breast & ovarian cancers. Mutations  20% Hereditary breast cancer, ovarian cancer, increased cancer risk in male carriers. Mutations  Sporadic breast cancers.  Li fraumeni syndrome Mutations - rare (<5%). Li fraumeni variant Increase breast cancer risk after radiation exposure
  6. 9. HER2/neu <ul><li>Human Epidermal growth factor Receptor2 </li></ul><ul><li>Member of ErbB protein family. </li></ul><ul><li>HER2 is a cell membrane surface-bound receptor tyrosine kinase - normally involved in signal transduction pathways  cell growth and differentiation. </li></ul><ul><li>Approximately 30 % of breast cancers  amplification of the  HER2/neu  gene/ overexpression of its protein product. </li></ul><ul><li>  Overexpression of this receptor in breast cancer  increased disease recurrence and worse prognosis. </li></ul>
  7. 10. PATHOGENESIS – HORMONAL FACTORS <ul><li>Excess Hormonal exposure  Sporadic cancers. </li></ul><ul><li>Post menopausal women  sporadic cancers  ER positive . </li></ul><ul><li>Hormones  breast growth during puberty, menstrual cycles, pregnancy  cycles of proliferation  cells at risk for DNA damage. </li></ul><ul><li>If premalignant or malignant cells are present, hormones - stimulate their growth + growth of normal epithelial and stromal cells  tumour development. </li></ul><ul><li>Metabolites of estrogen  mutations / generate DNA-damaging free radicals. </li></ul>
  8. 11. ESTROGEN DEPENDENT TUMOURS <ul><li>Approximately 75% of breast tumors  ”estrogen dependent.” </li></ul><ul><li>Tumors that do not rely on estrogen for growth  &quot; estrogen independent.&quot; </li></ul><ul><li>Estrogen dependence  predicted - presence of estrogen receptors in tumor cells. </li></ul><ul><li>The estrogen receptor protein - detected in breast tumor biopsy specimens  immunohistochemical staining. </li></ul><ul><li>Tumor cells that express estrogen receptors    ER positive- are usually estrogen dependent . </li></ul><ul><li>Tumors that lack estrogen receptors    ER negative-are usually estrogen independent. </li></ul>
  9. 12. <ul><li>> 95 % breast malignancies  ADENOCARCINOMAS </li></ul>
  10. 14. CLASSIFICATION – BREAST CARCINOMA <ul><li>NON-INVASIVE/IN SITU CARCINOMA </li></ul><ul><li>Intraductal carcinoma </li></ul><ul><li>Lobular carcinoma in situ </li></ul><ul><li>INVASIVE CARCINOMA </li></ul><ul><li>Infiltrating ( invasive ) duct carcinoma – NOS </li></ul><ul><li>Infiltrating ( invasive ) lobular carcinoma </li></ul><ul><li>Medullary carcinoma </li></ul><ul><li>Colloid (mucinous) </li></ul><ul><li>carcinoma </li></ul><ul><li>Papillary carcinoma </li></ul><ul><li>Tubular carcinoma </li></ul><ul><li>Adenoid cystic carcinoma </li></ul><ul><li>Secretory carcinoma </li></ul><ul><li>Inflammatory carcinoma </li></ul><ul><li>Carcinoma with metaplasia </li></ul><ul><li>PAGET’S DISEASE OF THE NIPPLE </li></ul>
  11. 15. <ul><li>Malignant clonal population of cells limited to ducts & lobules by the basement membrane. </li></ul>
  12. 16. DUCTAL CARCINOMA IN SITU <ul><li>Most DCIS  detected by calcifications on mammography /mammographic density - periductal fibrosis surrounding a DCIS/rarely palpable mass/ nipple discharge/incidental finding on a biopsy for another lesion. </li></ul><ul><li>Spreads through ducts & lobules  extensive lesions  entire sector of a breast. </li></ul><ul><li>DCIS – involves lobules – acini distorted, unfolded  appear as small ducts. </li></ul>
  13. 18. Comedocarcinoma <ul><li>Solid sheets of pleomorphic cells with high grade hyperchromatic nuclei. </li></ul><ul><li>Areas of central necrosis +nt. </li></ul><ul><li>Necrotic cell membranes – calcify  clusters/linear & branching microcalcifications on mammography. </li></ul><ul><li>Periductal concentric fibrosis & chronic inflammation. </li></ul><ul><li>Extensive lesions – palpable as vague nodularity. </li></ul>
  14. 19. Noncomedo DCIS <ul><li>Monomorphic cell population – nuclear grades  low to high. </li></ul><ul><li>CRIBRIFORM DCIS </li></ul><ul><li>Intra-epithelial spaces –evenly distributed, regular in shape. </li></ul><ul><li>COOKIE CUTTER – LIKE </li></ul><ul><li>SOLID DCIS </li></ul><ul><li>Completely fills the involved spaces. </li></ul>
  15. 20. Noncomedo DCIS <ul><li>PAPILLARY DCIS </li></ul><ul><li>Grows into spaces along fibrovascular cores  lack myoepithelial cell layer. </li></ul><ul><li>MICROPAPILLARY DCIS </li></ul><ul><li>Bulbous protrusions without a fibrovascular core arranged in complex intraductal patterns. </li></ul><ul><li>Calcifications – assoc.with necrosis/form on intraluminal secretions. </li></ul>
  16. 21. PAGET’S DISEASE OF NIPPLE <ul><li>Rare manifestation of breast CA. </li></ul><ul><li>U/l erythematous eruption, Pruritus. </li></ul><ul><li>Malignant cells/ PAGET CELLS  Extend from DCIS within ductal system – via lactiferous sinuses  nipple skin without crossing the BM. </li></ul><ul><li>Tumour cells – disrupt tight squamous epithelial barrier – ECF seeps out onto nipple surface  oozing scaly crust. </li></ul><ul><li>Paget’s cells – detected by nipple Bx/cytological preparation of the exudate. </li></ul><ul><li>Palpable mass  50 – 60 % of women => invasive CA. </li></ul><ul><li>No palpable mass => DCIS </li></ul><ul><li>Poorly differentiated, ER Negative, HER2/neu overexp. </li></ul><ul><li>Prognosis – depends on features of underlying Ca. </li></ul>
  18. 23. DCIS WITH MICROINVASION <ul><li>Area of invasion through BM  stroma - > 0.1 cm. </li></ul><ul><li>Assoc. with comedocarcinoma. </li></ul><ul><li>Few microinvasion foci  prognosis similar to DCIS. </li></ul>
  19. 24. MANAGEMENT AND PROGNOSIS OF DCIS <ul><li>MASTECTOMY for DCIS – curative  > 95 % pts. </li></ul><ul><li>Recurrence – rare – d/t residual DCIS in ducts in subcutaneous tissue – not removed during surgery/ d/t occult foci of invasion not detected at diagnosis. </li></ul><ul><li>Breast conservation – can be done but slightly higher risk of recurrence. </li></ul><ul><li>Major risk factors for recurrence: </li></ul><ul><li>Grade </li></ul><ul><li>Size </li></ul><ul><li>Margins </li></ul><ul><li>In ER + ve DCIS  Post-op. radiation + Tamoxifen  recurrence risk – low. </li></ul><ul><li>Death  < 2 % DCIS. </li></ul>
  20. 25. LOBULAR CARCINOMA IN SITU <ul><li>Incidental biopsy finding -no calcifications /stromal reactions  mammographic densities. </li></ul><ul><li>Bilateral - 20% to 40% . </li></ul><ul><li>Young women. </li></ul><ul><li>Loss of expression of E-cadherin (transmembrane cell adhesion protein  cohesion of normal breast epithelial cells). </li></ul>
  21. 26. LOBULAR CARCINOMA IN SITU - MORPHOLOGY <ul><li>Dyscohesive round cells with oval or round nuclei and small nucleoli. Absence of atypia, pleomorphism, mitoti activity, necrosis. </li></ul><ul><li>Involved acini – recognizable as lobules. </li></ul><ul><li>Mucin-positive signet-ring cells. </li></ul><ul><li>ER and PR +ve. </li></ul>
  22. 27. LOBULAR CARCINOMA IN SITU <ul><li>Invasive carcinoma  1% per year. </li></ul><ul><li>Both breasts - increased risk. </li></ul><ul><li>Risk - slightly higher in the </li></ul><ul><li>ipsilateral breast. </li></ul><ul><li>Invasive carcinomas - lobular type. </li></ul><ul><li>Treatment: </li></ul><ul><li>Bilateral prophylactic mastectomy. </li></ul><ul><li>Tamoxifen. </li></ul><ul><li>Close clinical follow-up. </li></ul><ul><li>Mammographic screening. </li></ul>
  23. 29. INVASIVE CARCINOMA – CLINICALFEATURES <ul><li>Palpable mass. </li></ul><ul><li>Axillary lymph node metastases </li></ul><ul><li>Fixity to the chest wall / skin dimpling. </li></ul><ul><li>Nipple retraction </li></ul><ul><li>Lymphatics - involved - block the local area of skin drainage  lymphedema , skin thickening. </li></ul><ul><li>Tethering of the skin to the breast by Cooper ligaments  peau d'orange . </li></ul><ul><li>Mammography  Radiodense mass </li></ul>
  24. 30. Invasive Carcinoma, No Special Type (NST; Invasive Ductal Carcinoma) <ul><li>Majority (70% to 80%). </li></ul><ul><li>Gross appearance: Most tumors - firm to hard ,irregular border . Less frequently - well-circumscribed border , softer consistency. </li></ul><ul><li>When cut / scraped  characteristic grating sound d/t small, central pinpoint foci or streaks of chalky-white elastotic stroma and occasional small foci of calcification. </li></ul>
  25. 31. Invasive Carcinoma – NST- HPE Features Well diff. Ca Mod. diff.Ca Poorly diff. Ca. Tubule formation Prominent Less,solid clusters/single infiltrating cells Ragged nests/solid sheets of cells Nuclei Small,round,monomorphic Greater nuclear pleomorphism Nuclei – enlarged,irregular. Mitotic figures Rare Present Numerous Proliferation rate - - High Tumour necrosis - - Present
  26. 32. INVASIVE LOBULAR CARCINOMA <ul><li>Palpable mass/ mammographic density with irregular borders. Sometimes - tumor infiltrates the tissue diffusely – little desmoplasia, not palpable, no mammographic density. Metastases – difficult to detect. </li></ul><ul><li>Bilateral - 5 – 10 %. </li></ul><ul><li>Biallelic loss of expression of ( CDH1 ,  encodes E-cadherin ) d/t mutations. </li></ul>
  27. 33. INVASIVE LOBULAR CARCINOMA <ul><li>Morphology: Histologic hallmark  dyscohesive infiltrating tumor cells, often arranged in single file or in loose clusters or sheets  INDIAN FILE APPEARANCE. </li></ul><ul><li>Tubule formation - absent. </li></ul><ul><li>Signet-ring cells containing an intracytoplasmic mucin droplet are common. </li></ul><ul><li>Desmoplasia - minimal or absent </li></ul>
  28. 34. INVASIVE LOBULAR CARCINOMA <ul><li>Well-differentiated and moderately differentiated carcinomas  diploid, ER positive, HER2/neu overexpression - rare </li></ul><ul><li>Poorly differentiated carcinomas  aneuploid, lack hormone receptors, may overexpress HER2/neu. </li></ul><ul><li>Different pattern of metastasis than other breast cancers. Metastasis  peritoneum ,retroperitoneum, the leptomeninges (carcinoma meningitis), the gastrointestinal tract, ovaries and uterus. </li></ul>
  29. 35. MEDULLARY CARCINOMA <ul><li>MC - 6 th decade. </li></ul><ul><li>May closely mimic a benign lesion clinically and radiologically/ present as a rapidly growing mass. </li></ul><ul><li>MORPHOLOGY : Well – circumscribed,soft,fleshy mass - little desmoplasia  more yielding on palpation and cutting. ( medulla =>“marrow”). </li></ul>
  30. 36. MEDULLARY CARCINOMA - HPE <ul><li>Solid, syncytium-like sheets of large cells with vesicular, pleomorphic nuclei, prominent nucleoli  > 75% of the tumor </li></ul><ul><li>Frequent mitotic figures; </li></ul><ul><li>Moderate to marked lymphoplasmacytic infiltrate surrounding and within the tumor. </li></ul><ul><li>Pushing (noninfiltrative) border. </li></ul><ul><li>Poorly differentiated. </li></ul>
  31. 37. MEDULLARY CARCINOMA <ul><li>High nuclear grade, aneuploidy, hormone receptors - nt, HER2/neu overexpression –nt. </li></ul><ul><li>Lymph node metastases - infrequent. </li></ul><ul><li>Syncytial growth pattern and pushing borders - d/t overexpression of adhesion molecules  intercellular cell adhesion molecule and E-cadherin  limit metastatic potential. </li></ul>
  32. 38. MUCINOUS/COLLOID CARCINOMA <ul><li>Older women (median age 71)  grow slowly - many years. </li></ul><ul><li>Morphology: Tumor – soft/rubbery . Consistency & appearance of pale gray-blue gelatin. Borders - pushing / circumscribed. </li></ul>
  33. 39. MUCINOUS CARCINOMA - HPE <ul><li>Tumor cells - arranged in clusters and small islands within large lakes of mucin. </li></ul><ul><li>Mucinous carcinomas  diploid, well to moderately differentiated, and ER positive. </li></ul><ul><li>Lymph node metastases - uncommon. </li></ul><ul><li>Overall prognosis is slightly better. </li></ul>
  34. 40. TUBULAR CARCINOMA <ul><li>Small irregular mammographic densities - late 40s. </li></ul><ul><li>Uncommon. </li></ul><ul><li>Morphology: Well-formed tubules + nt, myoepithelial cell layer, BM - nt  tumor cells in direct contact with the stroma. Apocrine snouts - typical.Calcifications - within the lumens. </li></ul><ul><li>> 95% of all tubular carcinomas - diploid, ER + ve,HER2/neu –ve . </li></ul><ul><li>Well differentiated. Excellent prognosis. </li></ul>
  35. 41. INVASIVE PAPILLARY & MICROPAPILLARY CARCINOMA <ul><li>Rare - 1% or fewer of all invasive cancers. </li></ul><ul><li>More commonly seen in DCIS. </li></ul><ul><li>INVASIVE PAPILLARY CA. </li></ul><ul><li>ER positive. </li></ul><ul><li>Favorable prognosis. </li></ul><ul><li>INVASIVE MICROPAPILLARY CA. </li></ul><ul><li>ER negative,HER2 positive. </li></ul><ul><li>Lymph node metastases - very common </li></ul><ul><li>Prognosis is poor. </li></ul>
  36. 42. INFLAMMATORY CARCINOMA <ul><li>Tumors  swollen, erythematous breast - caused by extensive invasion and obstruction of dermal lymphatics by tumor cells. </li></ul><ul><li>Underlying carcinoma - diffusely infiltrative - does not form a discrete palpable mass  confusion with true inflammatory conditions a  delay in diagnosis. </li></ul><ul><li>Many patients  metastases at diagnosis / recur rapidly. </li></ul><ul><li>Overall prognosis  poor. </li></ul>
  37. 43. METAPLASTIC CARCINOMA <ul><li>Includes a variety of rare types of breast cancer (<1% of all cases)  matrix-producing carcinomas, squamous cell carcinomas, and carcinomas with a prominent spindle cell component. </li></ul><ul><li>ER-PR-HER2/neu “triple negative”. </li></ul><ul><li>Lymph node metastases - infrequent. </li></ul><ul><li>Prognosis - poor. </li></ul>
  38. 44. PROGNOSTIC FACTORS - MAJOR <ul><li>Outcome in breast CA – varies widely. </li></ul><ul><li>Prognosis – determined by pathologic examination of primary carcinoma & axillary lymph nodes. </li></ul><ul><li>American Joint Committee on Cancer (AJCC) staging system  divides patients into five stages (O to IV)  correlated with survival. </li></ul><ul><li>Major prognostic factors  strongest predictors of death. </li></ul><ul><li>Invasive vs insitu CA. </li></ul><ul><li>Distant metastasis </li></ul><ul><li>Lymph node metastasis </li></ul><ul><li>Tumour size </li></ul><ul><li>Locally advanced ds. </li></ul><ul><li>Inflammatory CA. </li></ul>
  39. 45. Stage T: Primary Cancer Lymph Nodes (LNs) M: Distant Metastasis 5-Year Survival (%) 0 DCIS or LCIS No metastases Absent 92 I Invasive carcinoma ≤2 cm No metastases Absent 87 II Invasive carcinoma >2 cm No metastases Absent 75 Invasive carcinoma <5 cm 1 to 3 positive LNs Absent III Invasive carcinoma >5 cm 1 to 3 positive LNs Absent 46 Any size invasive carcinoma ≥ 4 positive LNs Absent Invasive carcinoma with skin or chest wall involvement or inflammatory carcinoma 0 to >10 positive LNs. Absent IV Any size invasive carcinoma Negative or positive lymph nodes Present 13
  41. 51. FIBROADENOMA <ul><li>MC benign tumor - 2 nd & 3 rd decade.Multiple, bilateral. </li></ul><ul><li>Young women  palpable mass. Older women  mammographic density / calcifications. </li></ul><ul><li>Epithelium – hormonally reponsive  increase in size during lactation  complicated by inflammation, infarction  mimics CA. </li></ul><ul><li>Stroma - densely hyalinized after menopause -may calcify. Large lobulated (“popcorn”) calcification s  characteristic mammographic appearance. </li></ul><ul><li>Small calcifications - clustered -require biopsy to exclude carcinoma. </li></ul>GROSS: Spherical, sharply circumscribed, rubbery, grayish white, freely movable nodules -bulge above the surrounding tissue and contain slitlike spaces. < 1 cm – large tumors.
  42. 52. FIBROADENOMA - HPE <ul><li>Stroma – delicate, cellular,myxoid-resembles normal intralobular stroma. </li></ul><ul><li>Epithelium - surrounded by stroma - compressed & distorted by it. </li></ul><ul><li>Risk of malignancy  assoc. with Complex fibroadenomas  cysts > 0.3 cm. in size, sclerosing adenosis, epithelial calcifications, papillary apocrine change. </li></ul>
  43. 53. FIBROADENOMA - TYPES <ul><li>INTRACANALICULAR </li></ul><ul><li>PERICANALICULAR </li></ul>In  pericanalicular  histologic pattern, the  glands maintain their round or oval profiles.  There is  no prognostic or clinical significance  attached to the pericanalicular and intracanalicular patterns. Both may be seen within the same lesion. 
  44. 54. PHYLLODES TUMOUR  Phyllodes – leaf-like <ul><li>Arise from intralobular stroma. </li></ul><ul><li>Any age, most – 6 th decade. </li></ul><ul><li>Majority  palpable masses, few found by mammography. </li></ul><ul><li>Cystosarcoma phyllodes – Misnomer. </li></ul><ul><li>MORPHOLOGY : Few cms. to massive lesions involving the entire breast Larger lesions  bulbous protrusions d/t the presence of nodules of proliferating stroma covered by epithelium . Some tumors - protrusions extend into a cystic space. </li></ul>
  45. 55. PHYLLODES TUMOUR <ul><li>HPE: Greater cellularity, mitotic rate, nuclear pleomorphism, stromal overgrowth, and infiltrative borders. </li></ul><ul><li>Recur locally, rare metastases. </li></ul><ul><li>Majority  Low-grade lesions </li></ul><ul><li>Rare  High-grade lesions. </li></ul><ul><li>Phyllodes tumors - excised with wide margins / mastectomy to avoid local recurrences. </li></ul>
  46. 57. NORMAL MALE BREAST <ul><li>Consists of the nipple and a rudimentary duct system ending in terminal buds without lobule formation . </li></ul>
  47. 58. GYNAECOMASTIA <ul><li>Enlargement of male breast. </li></ul><ul><li>Puberty/very aged/hyperestrinism. </li></ul><ul><li>Cirrhosis of liver, Increased adrenal estrogens as androgenic functions of testis fail in very aged, Drugs – alcohol, marijuana, heroin, ART, anabolic steroids used by atheletes & body builders, Klinefelter syndrome. </li></ul><ul><li>D/t imbalance between estrogens,  stimulate breast tissue and androgens  which counteract these effects </li></ul><ul><li>Unilateral or bilateral </li></ul><ul><li>Button-like subareolar enlargement. </li></ul><ul><li>Morphology : Increase in dense collagenous connective tissue, marked micropapillary epithelial hyperplasia of the duct lining. Individual epithelial cells  fairly regular, columnar to cuboidal cells with regular nuclei. Lobule formation is rare. </li></ul>